ResistSOS
Financiado
Overcoming Resistance to Anti-cancer Drugs by Blocking Mutation-prone DNA Polyme...
Overcoming Resistance to Anti-cancer Drugs by Blocking Mutation-prone DNA Polymerases and the SOS Response
Background: A large fraction of cancer patients die because their tumors initially respond to drugs but later they evolve tolerance. Thus, resistance to diverse drugs, along with the soaring costs of new treatments, are emerging a...
Background: A large fraction of cancer patients die because their tumors initially respond to drugs but later they evolve tolerance. Thus, resistance to diverse drugs, along with the soaring costs of new treatments, are emerging as major societal issues of the 2020s. Herein, we explore one of the most distressful examples, tolerance of lung cancer to EGFR-specific tyrosine kinase inhibitors (TKIs).
Working hypothesis: In similarity to bacteria exposed to antibiotics, when cancer cells are exposed to TKIs they enlist SOS responses, which activate endogenous mutators. Hence, we will combine the relatively effective but mutagenic TKIs with drugs that disarm the mutators. This scheme will be applied on models of EGFR+ lung cancer, a disease that repeatedly evolves mutations and resistance, but eventually leaves millions of patients with no treatment choices.
Specific aims: Our initial studies identified one triad of the SOS system: a sensor of cell death - GAS6, a mediator - AXL, GAS6’ receptor, and a mutator - low-fidelity DNA polymerases. Remarkably, blocking AXL using an antibody irreversibly prevented relapses when combined with EGFR inhibitors. Along with establishing this triad, we will employ transcriptomics, protetomics and metabolomics to resolve parallel mutators and sensors. Likewise, we will explore alternative ways to block resistance, for example by directly targeting DNA polymerases, MYC and purine metabolism. Aiming at strategies that minimize SOS enlisting, we will explore the premise of boosting immune destruction of cancer cells.
Significance: According to the current status quo, next-generation inhibitors are being applied when resistance emerges. However, this scheme does not cure, only buys time. ResistSOS offers an alternative that might eradicate resistance and cure disease models following treatments that are based on deep understanding and blocking the mutagenic SOS response.
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Duración del proyecto: 64 meses
Fecha Inicio: 2023-05-24
Fecha Fin: 2028-09-30
Fecha Fin: 2028-09-30
Línea de financiación: concedida
El organismo HORIZON EUROPE notifico la concesión del proyecto el día 2023-05-24
Línea de financiación objetivo
El proyecto se financió a través de la siguiente ayuda:
ERC-2022-ADG:
ERC ADVANCED GRANTS
Cerrada
hace 2 años
Presupuesto
El presupuesto total del proyecto asciende a
3M€
Líder del proyecto
WEIZMANN INSTITUTE OF SCIENCE
No se ha especificado una descripción o un objeto social para esta compañía.
Perfil tecnológico
TRL
4-5
Perfil tecnológico
TRL
4-5